EFFECTS OF CHEMICAL DENERVATION WITH 6-HYDROXYDOPAMINE ON MYOCARDIAL RESPONSIVENESS TO ISOPROTERENOL IN RABBITS

This study examined the hypothesis that chemical denervation with 6-hy droxydopamine (6-OHDA) would increase myocardial responsiveness to iso proterenol. Five days previously, 15 New Zealand white rabbits were gi ven 60 mg/kg 6-OHDA intravenously. Fifteen control rabbits received ve hicle. Hemodynamic, coronary blood flow (CBF): and cardiac output meas urements were obtained before and during isoproterenol infusion (0.5 m u g/kg/min for 15 min). Norepinephrine tissue content, beta-adrenocept or number (Bmax) and affinity (Kd), cyclic AMP content and cyclic AMP- phosphodiesterase (PDE) activity were measured in the subepicardium (E PI) and subendocardium (ENDO). Myocardial norepinephrine content was s ignificantly decreased from 1263 +/- 292 (EPI) and 874 +/- 221 ng/g ti ssue (ENDO) in the control to 148 +/- 33 (EPI) and 90 +/- 45 ng/g tiss ue (ENDO) in the denervated group. There were no significant changes i n cyclic AMP-PDE activity or Bmax and Kd of beta-adrenoceptors. Cyclic AMP content was similar at baseline, but controls had a significantly larger increase (123 - 155%) during isoproterenol infusion when compa red to the denervated group (27 - 37%). The denervated animals showed a smaller increase in cardiac output during isoproterenol infusion (fr om 203 +/- 30 to 235 +/- 26 ml/min), when compared to the control anim als (from 135 +/- 18 to 216 +/- 42 ml/min). Baseline CBF was significa ntly higher in the EPI but not ENDO of the denervated group (185 +/- 2 0 ml/100 g/min in EPI and 150 +/- 8 in ENDO) compared to the control g roup (108 +/- 13 in EPI and 133 +/- 17 in ENDO). The relative increase in CBF during isoproterenol infusion was smaller in the denervated gr oup (44 - 45%) than the control group (107 - 109%). Isoproterenol infu sions of 0.1 and 2.5 mu g/kg/min showed similarly depressed coronary b lood flow responses in denervated animals. Thus, the chemically denerv ated animals did not have beta-adrenoceptor upregulation, exhibited a lesser increase in cyclic AMP with isoproterenol, and had a reduced fu nctional and coronary blood flow response to isoproterenol. This occur red without any significant change in beta-adrenoceptor number or affi nity, or in cyclic AMP-phosphodiesterase activity, indicating there ma y be receptor uncoupling or other changes in the signal transduction p athway.